DESCRIPTION: Kidney disease is the fourth-leading contributor to death in HIV-infected persons and HIV-associated nephropathy (HIVAN) is the most common cause of end stage renal disease in this population. Moreover, HIV-infected persons are at increased risk of developing diabetes mellitus and HIV infection increases the risk of progressive chronic kidney disease (CKD) in patients with diabetes. Antiretroviral therapy (ART) is often effective in treatin patients at risk for HIVAN but the mechanism by which it protects the kidney is unclear since animal models suggest that viral replication is not required for HIVAN pathogenesis. The effects of ART upon renal outcomes in HIV infected patients with non-HIVAN kidney diseases such as diabetic nephropathy are not clear. The results of a recently published clinical study suggest that HIV protease inhibitors may be efficacious in HIV negative patients with CKD, indicating that these medications may protect the kidney via mechanisms that are independent of effects on viral replication. Our long-term goal is to understand the mechanisms by which HIV infection predisposes patients to CKD to facilitate development of novel strategies to prevent and treat kidney disease in this vulnerable population. The objective of this proposal is to identify novel mechanisms by which ART may prevent the progression HIV-associated kidney diseases. Our central hypothesis is that ART may protect the kidney against HIV-induced epithelial injury and inflammatory response via mechanisms that are independent of suppression of HIV replication. Our hypothesis is supported by data from our lab and others demonstrating that: 1) renal epithelial expression of Vpr and/or Nef are sufficient to induce HIVAN in the absence of viral replication; 2) ART can ameliorate HIVAN in patients without decreasing renal epithelial HIV expression; 3) HIV protease inhibitors have efficacy in the treatment of non- HIV related kidney disease; 4) preliminary data suggesting that HIV protease inhibitors protect the kidney from deleterious effects of HIV gene expression and non-HIV renal injury. The rationale for the proposed work is that better understanding how ART protects against HIV-related kidney diseases will enable new strategies to prevent and treat kidney disease. We will test our hypothesis and address critically important questions in two specific aims. In our first specific aim, we will use HIV-transgenic murine models of kidney disease to elucidate the HIV-independent effects of ART in preventing and treating HIVAN and diabetic glomerular injury. In our second specific aim, we will perform a series of studies to determine the molecular mechanisms by which ART protects kidney cells from the deleterious effects of HIV independent of effects on HIV replication, including novel studies to decipher the role of AMP-kinase in mediating the renoprotective effects of protease inhibitors. We propose innovative approaches to discover novel mechanisms by which ART protects the kidney from HIV and other insults. These results will have a positive impact because they will provide new insights that will improve our ability to prevent and treat kidney disease in persons living with HIV/AIDS.